Immunological tolerance of self constituents is a dynamic process. Self tolerance is constantly renewed by the presence of self antigens during the maturation of immunocompetent stem cells. During advance age in both human beings and mice there is an increased incidence of autoimmunity. It has been shown that aged mice are more resistant to the induction of experimental acquired immunological toleance. The experiments proposed here examine the cellular bases for declining self tolerance in aging. First, the reduced susceptibility for tolerance induction will be sought in central and peripheral lymphoid populations. Second, the role of lipopolysaccharide (LPS) from gram negative bacteria in inducing the formation of immunoregulatory monokine(s) and in effecting the expression of autoantibody forming cells in aging will be investigated. The cellular basis of tolerance sensitivity in aged mice will be examined using acquired immunological tolerance to DHGG (deaggregated human IgG) in mice as a model for self tolerance. The sensitivity of peripheral lymphoid cells, i.e., splenocytes and splenic B and T lymphoid subpopulations, to the induction of unresponsiveness in an adoptive host will be investigated. This system will be used so that it will be possible to distinguish between intrinsic lymphocyte changes with aging as they relate to tolerance induction and other factors such as changed antigen metabolism. Similarly, the capacity of bone marrow stem cells to be rendered unresponsive will be investigated. The role of suppressor cells in tolerance in aging will be investigated using the adoptive transfer system and cyclophosphamide to modulate the function of these cells. LPS has many effects of both the induction and termination of tolerance to HGG. In addition, LPS preferentially stimulates autoreactive clones in aged mice. The cellular mechanisms of the age related increased sensitivity to LPS will be investigated. Specifically, the induction of Interleukin 1 (IL-1) by LPS in cells of mice of different ages will be studied. Conversely, the sensitivity of senescent cells to this monokine will be compared to that of young cells. The role of IL-1 in mediating thermoregulatory effects of LPS will be investigated. LPS induces other immunoregulatory substances, e.g., tumor necrosis serum. The effect of age on these functions will also be sought.